The goal of this project is to investigate changes in the temporal dynamics of cholinergic modulation during aging and the extent to which these changes contribute to alterations of network activity in hippocampal area CA3 that can result in age-related memory loss and cognitive decline, the hallmarks of Alzheimer’s disease. A major deliverable of the project is a biologically realistic, full-scale spiking neural network model of hippocampal CA3 that will include simulations of temporal dynamics in cholinergic modulation as a function of animal behavior in the context of encoding and retrieval of behaviorally-relevant information. To achieve this goal, we will acquire a high-quality experimental dataset on neural firing in area CA3 and temporal dynamics of cholinergic modulation using parallel recordings of multiple single units in CA3 and fiber photometry recordings of septo-cholinergic projection neurons or acetylcholine release in the hippocampus in freely behaving mice performing a hippocampus-dependent spatial memory task. Tightly interrelated computational modeling will implement a data-driven, biophysically detailed, real-scale spiking neural network simulation of the CA3 circuit at the level of individual neurons and synapses to investigate encoding and retrieval dynamics during distinguishable behavioral activities requiring the acquisition or recall of information. Experiments in aged mice and quantitative analysis of in silico recordings using data from young and aged mice will generate testable hypotheses on the functional role of distinct neuron types for specific network patterns associated with spatial memory and pattern completion that will allow the mechanistic investigation of the effects of cholinergic modulation on neural activity underlying encoding, storage, and retrieval of memory traces and their changes during aging, the major risk factor for developing Alzheimer’s disease. The in silico model will also explore quantitative effects of muscarinic and nicotinic receptors on individual neuron types within CA3 and mechanisms such as runaway synaptic modification and structural plasticity possibly underlying the changes in memory encoding and retrieval observed in aged mice. The data-driven biologically realistic CA3 circuit simulations will foster the formulation of novel, specific, and testable hypotheses of memory impairment that will be tested and quantified in closed-loop optogenetic manipulations of temporal dynamics in cholinergic modulation in freely behaving mice that aim at either disrupting or restoring hippocampal network patterns in young or aged mice, respectively. We expect the results of this interdisciplinary collaborative project to advance our understanding of temporal dynamics in the encoding and retrieval of spatial memories, the contribution of fast cholinergic modulation to this process, and how changes in temporal dynamics can result in maladaptive changes on the synaptic, cellular, or network level that may contribute to further memory loss and cognitive decline during aging, preceding and potentially causing the development of Alzheimer’s disease.
